tbuckley/cabot-search huggingface dataset:
P17.19.B Incidence of treatment-associated imaging changes in newly diagnosed MGMT promoter-methylated glioblastoma treated with cilengitide (EORTC 26071 - CENTRIC study): interim analysis
Authors: C M Flies, M Friedrich, P Lohmann, K van Garderen, M Smits, J C Tonn, M Weller, N Galldiks, T J Snijders
Journal: Neuro-Oncology (2022)

Abstract Background In patients with glioblastoma, radiological recurrence of enhancing tissue after chemoradiotherapy can originate from progressive disease (PD) or from pseudoprogression/treatment-associated changes. There are no widely approved consensus criteria for treatment-associated changes. In the randomised EORTC-CENTRIC study (NCT00689221), patients with MGMT promoter-methylated glioblastoma were treated with chemoradiotherapy or chemoradiotherapy with cilengitide, an integrin inhibitor. We assessed the rate of treatment-associated changes in these groups according to the modified response assessment in neuro-oncology (RANO) criteria of 2017. Methods CENTRIC patients from both study arms with ≥3 follow-up MRIs were included. Preliminary PD (PPD) was defined as a ≥25% increase of the sum of perpendicular diameter (SPD) of a new or increasing lesion compared to baseline or nadir on the T1-MRI with gadolinium. Subsequent PD was defined as a second ≥25% increase of the SPD, at least 4 weeks later, or as a new lesion outside the radiation field. Treatment-associated changes were defined as stabilisation on ≥2 follow-up MRIs after PPD, each one 4 weeks later, or partial/complete regression on ≥1 follow-up MRI 4 weeks later. Results In total, 4,051 MRIs from 584 patients were available. This interim analysis included data on 462 patients with similar proportions in the cilengitide and control arm (50.9% and 49.1%). Due to missing MRIs or values, 128 were excluded. Of the remaining 334 patients, 157 (47%) patients showed RANO measurable disease at baseline or nadir (median SPD, 0mm2; interquartile range (IQR) 552.1 (0-552.1). After chemoradiotherapy with or without cilengitide, PPD occurred in 214 patients (64.1%) after a median time of 6.08 months after finishing radiation (IQR 11.4 (2.4-13.8), and 3.65 months after baseline or nadir (IQR 6.4 (2.1-8.5). After follow-up of these 214 patients, treatment-associated changes were diagnosed in 62 (18.6%) and PD was diagnosed in 48 (14.4%). The remaining 104 (31.1%) patients had no further follow-up MRI after PPD, mostly because a clinical decision to call PD was made. In the cilengitide group of 178 patients, 37 (20.8%) patients developed treatment-associated changes, and 23 (12.9%) patients developed PD, whereas in the control group of 156 patients, 25 (16%) patients developed treatment-associated changes, and 25 (16%) patients PD. Conclusion With the modified RANO criteria, the rate of treatment-associated changes was low compared to previous studies in newly diagnosed MGMT promoter-methylated glioblastoma. This rate did not change with addition of cilengitide. RANO-recommended radiological follow-up was not always awaited, which reflects clinical practice. Full data will be presented.
P11.16.A Questioning convention - is intrathecal chemotherapy (ITC) necessary for patients with newly diagnosed primary central nervous system lymphoma (PCNSL): combined results from three independent cohorts
Authors: K Tuohy, D Aregawi, S Seidel, L Rieger, O Klapschus, B Zacharia, A Korfel, U Schlegel, M Glantz
Journal: Neuro-Oncology (2022)

Abstract Background Despite beguiling responses to initial therapy in many patients, PCNSL remains a therapeutic challenge. Relapse is common, cures are elusive for most patients, and overall response are disappointing compared to other diffuse large B-cell lymphomas. High-dose methotrexate-based therapies have become the standard of care, with many variations, but there is no consensus, and very little data regarding the role of ITC in the initial treatment of patients with PCNSL. Material and Methods We collected study-level and where possible, patient-level data from three independent clinical trials comparing adults with newly diagnosed PCNSL treated with regimens that differed based on the use of ITC. Patient characteristics, overall (OS) and progression-free survival (PFS), and characteristics of relapse were examined. The frequency of lymphomatous meningitis at diagnosis based on the location of CSF sampling - ventricular vs. lumbar - was also investigated. Complete data retrieval for this updated analysis has allowed us to combine data from the three studies and calculate summary statistics using a random effects model and inverse variance technique. In addition, predictors of OS and PFS were modeled using a Cox proportional hazards technique. Results The three cohorts were treated with: HD MTX/rituximab/ifosfamide followed by either HD MTX/cytarabine/ifosfamide (group Ia), or cytarabine/thiotepa and autologous stem cell transplant (group Ib) (n=80); HDMTX/vinca alkaloids/ifosfamide/cytarabine (group II) (n=83); or HD MTX/rituximab (group III) (n=49). ITC consisted of MTX/cytarabine/prednisolone (group Ia only, n=43); MTX/cytarabine/prednisolone (group II, n=65); or liposomal cytarabine (group III, n=21). One- and two-year OS was better in the ITC chemotherapy compared to the no-ITC group (RR 1.25 [1.16-1.34] and 1.20 [1.14-1.26] respectively, p&amp;lt; 0.001 for both comparisons). One-year PFS was also improved in the ITC group (RR 1.12 [1.01-1.25], p=0.031). Two-year PFS was not statistically different between groups (RR 1.20 [0.90-1.59], p=0.220). Relapse involving the CSF was more frequent in the non-IT chemotherapy group (RR 2.31 [2.03-2.62], p&amp;lt; 0.001). CSF cytology was positive in 81% of ventricular specimens vs 14.3% of lumbar specimens (p&amp;lt; 0.001). Conclusion This analysis of three independent cohorts of adults with newly diagnosed PCNSL suggests (when ventricular rather than lumbar CSF is sampled) that lymphomatous meningitis is dramatically more frequent, and perhaps universal. Including ITC as part of the initial treatment regimen increased both OS and PFS substantially. A randomized controlled trial is urgently required.
P11.35.B The clinical course of long-term survivors after the diagnosis of brain metastasis
Authors: S T Jünger, A Meissner, M I Ruge, D Rueß, R Goldbrunner, S Grau
Journal: Neuro-Oncology (2022)

Abstract Background To asses demographic and clinical parameters, treatment, and course of disease in patients surviving longer ≥ 5 years after the diagnosis of brain metastasis (BM). Material and Methods We retrospectively identified patients who were treated for BM and survived ≥ 5 years after initial BM diagnosis. We analysed and described clinical and treatment related parameters with respect to histology, time to occurrence and systemic/ BM-specific treatment. Results We included 48 patients with a mean age of 55 years (range 33-81, SD 12) at diagnosis of primary tumor and 58 (range 41-84, SD 20) at initial BM diagnosis. Histology was non-small-cell lung cancer in 18 (37.5%), melanoma in 14 (29.2%), breast cancer in 11 (22.9%), renal carcinoma in 2 (4.2%), and small-cell lung cancer, cancer of unknown primary and gastrointestinal cancer in one case each (2.1%). Treatment for primary tumor included resection (83.3%), chemotherapy (43.8%), radiation (33.3%), interferon therapy (18.8%), and immuno-/targeted therapy (25%). Most patients received a combination of latter. The mean interval between primary tumor and BM diagnosis was 36 months (range -2 to 277; SD 57). At the time of BM diagnosis, 50% of patients presented with systemically stable disease, 66.7% showed BM related symptoms, 92% showed a KPS ≥70. Most patients had 1 BM (72.9%), while 20.9% had 2-3 and 6.3% &amp;gt;3. Initial treatment for BM comprised resection (60.4%), stereotactic radiosurgery (27.2%), whole-brain-radiation therapy (8.4%), and interstitial brachytherapy (4.2%). Approximately half of the patients (52.1%) suffered from ≥1 BM relapse at initial treatment site. At the time of the analysis, 13 (27.1%) patients had died; cause of death was mostly unknown, in two patients each, systemic/cerebral cause was confirmed. The mean overall survival (OS) was 131 months (range 64-344, SD 68) and 95 (range 60-246, SD 36) after diagnosis of primary tumor and BM, respectively. All patients suffering from melanoma who had received interferon therapy (n=8) survived. Neither systemic status at BM diagnosis nor the administration of novel treatment agents or chemotherapy after BM diagnosis showed an impact on OS (p=0.642, p=0.177 and p=0.628, respectively). Further survival analysis was omitted due to subgroup sizes. Conclusion Despite the usually fatal course after BM development, some patients show long-term survival. Whether specific genetic parameters have a particular impact in this subgroup of patients, warrants further investigation.
P10.21.B Pharmacogenomics profiling of gliomas for precision medicine
Authors: A Lipsa, A Hau, L Ermini, R Toth, A Oudin, B Klink, F Hertel, M Mittelbronn, A Golebiewska, S Niclou
Journal: Neuro-Oncology (2022)

Abstract Background Molecular characterization based on genomic, transcriptomic and epigenetic profiling has led to a better delineation of various glioma subtypes and highlighted the individual paths of glioma evolution upon treatment and recurrence. However, due to cellular and molecular diversity of these tumors, the pharmacological treatment of gliomas, in particular of its most malignant subtype Glioblastoma (GBM), remains a major challenge. To address this challenge, we here apply a pharmacogenomics approach, modelling the disease in matched patient-derived preclinical models and profiling the differential drug response among individual patients and glioma subtypes Material and Methods We generated a cohort of 45 Patient-Derived Orthotopic Xenografts (PDOX) from a collection of over 400 glioma patients. We used a multi-parametric approach based on genetic, transcriptomic and longitudinal profiling of patients and their matched xenografts for a comprehensive subgrouping of our glioma cohort. Based on PDOX-derived 3D tumor organoids we carried out a targeted drug screen focused on epigenetic regulators. A high throughput drug screening using an unbiased large chemical library containing a unique collection of FDA approved compounds with high pharmacological diversity is currently ongoing. Results Our glioma cohort with matched PDOX and 3D tumor organoids represents diverse subgroups of glioma patients, including a unique collection of primary and relapsed tumors from the same patient. Our preliminary drug screen analysis on 3D organoids highlights selective susceptibility to certain epigenetic inhibitors in primary disease but not in the same patient’s relapse. Results of matching genomics and functional data will be presented. Conclusion An integrated personalized approach to profile gliomas at multiple genomic and functional levels allows for pharmacogenomic subgrouping of patients for personalized treatment strategies. This analysis will allow to link genotypes to functional phenotypes and hopefully identify therapeutic options for selected glioma sub-populations.
P12.07.B Getting to the core of microglia versus bone marrow-derived macrophages in glioblastoma
Authors: Z R Woolf, A Smith, M E V Swanson, E L Scotter, P Schweder, J Correia, T I Park, M Dragunow
Journal: Neuro-Oncology (2022)

Abstract Background Microglia and bone marrow-derived macrophages (BMDMs) are two ontogenetically distinct myeloid populations present within glioblastoma that can comprise 30-50% of the tumour mass. Historically, these cell types have been conflated and studied as a single population of ‘tumour-associated macrophages’. Recent advances in single-cell omics have allowed population delineation, suggesting microglia and BMDMs may play different roles within the tumour and subsequently differentially affect tumour progression. Despite building evidence for the unique functions of these cells within glioblastoma, the inherent heterogeneity of the tumour landscape has complicated such studies. Indeed, macrophages exist as phenotypically and functionally diverse populations that are polarised in a context-dependent manner. Hence, to understand the differences between microglia and BMDMs within glioblastoma, both ontogeny and spatial location must be considered. Material and Methods To elucidate the functional roles of microglia and BMDMs across the tumour landscape, a publicly available RNAseq dataset was utilised to classify myeloid cells into four populations based on spatial location and ontogeny. These were tumour core BMDMs and microglia, or tumour periphery BMDMs and microglia. Differential gene analysis was then performed to identify significant differentially expressed genes (DEGs) between classified myeloid populations. Tumour core DEGs were then compared against the Ivy Glioblastoma Atlas to define their expression across anatomical tumour regions. Finally, myeloid DEGs were validated at the protein level on human glioblastoma tissue through immunohistochemistry. Results Microglia and BMDMs showed different spatial distributions across the tumour landscape and displayed distinct functional expression profiles. Microglia held a more chemotactic and pro-inflammatory profile, whereas BMDMs held a more pro-tumoural profile. However, a comparison of microglia between the tumour core and periphery revealed that tumour microglia upregulate many pro-tumoural genes, including multiple genes that have previously been defined as ‘BMDM-enriched’. Moreover, we found myeloid DEGs identified within the tumour core cluster to distinct spatial tumour regions such as the vascular or hypoxic niche. Immunohistochemical staining reflected these spatial expression profiles, identifying a distinct population of phagocytic macrophages within the hypoxic niche. Conclusion Although microglia and BMDMs represent two ontogenetically distinct myeloid populations within glioblastoma, both cell types can adopt similar functional expression profiles within the tumour core, particularly within tumour niches. This indicates that myeloid cell function is strongly influenced by the tumour microenvironment, rather than ontogeny alone.
P11.73.B The diagnostic value of frame-based stereotactic biopsies in the age of precision oncology: A cross-sectional study
Authors: O T Alhalabi, F Sahm, A W Unterberg, M Jakobs
Journal: Neuro-Oncology (2022)

Abstract Background For non-resectable, eloquent, multifocal and deep-seated intracranial lesions, stereotactic frame-based biopsies can deliver a finite amount of tissue for neuropathology studies. With the increasing role of molecular genetics in the diagnostics of intracranial tumors, sufficient tissue for sequencing studies is of paramount importance. This study explored the rate of successful diagnosis after stereotactic frame-based biopsies of intracranial lesions in a high-throughput neurooncology center Material and Methods 145 consecutive patients undergoing frame-based stereotactic biopsies in 2020 and 2021 at our neurosurgical department were included in this retrospective analysis. Aspects of histological and molecular (methylomics, panel-sequencing) neuropathology analysis in addition to clinical and radiological variables were analyzed. Cases were classified as conclusive, likely-conclusive (sufficient diagnosis with non-satisfying sequencing information), and inconclusive neuropathological diagnosis. Results Of 145 cases analyzed, astrocytic tumors were suspected in n= 94 (67%) of patients. In n= 122 cases (84%), a conclusive diagnosis was possible. For 14 (11%) cases, a likely-conclusive diagnosis was established Diagnoses comprised mainly WHO 4 glioblastomas (56%), WHO 3 gliomas (2%) in addition to WHO 1 and 2 gliomas (n=7, 5%), CNS lymphomas (n=23, 16%), inflammatory diseases (n=10, 7%) and normal or reactive tissue (n=4, 3%). Methylomics were pivotal in providing an integrated diagnosis in 30% of the cases (panel sequencing in 14%). In n= 12 (8%) of the cases further testing was hindered by insufficient tissue sample DNA. Only in 3 out of 12 cases this resulted in a final inconclusive diagnosis. Conclusion Although stereotactic frame-based biopsies deliver a limited amount of tissue, they bear an excellent histopathological and molecular genetic diagnostic yield, with rare cases of missing molecular data or rarely insufficient diagnosis. Optimizing the number and representativeness of cell and DNA-rich stereotactic biopsy specimen might enhance the diagnostic and therapeutic potential of precision oncology even further.
JS07.4.A Correspondence of glutamine and glycine imaging based on 7T MRSI to amino acid PET
Authors: G Hangel, I Rausch, J Furtner, T Roetzer-Pejrimovsky, M Preusser, W Bogner, K Rössler, S Trattnig, T Traub-Weidinger, G Widhalm
Journal: Neuro-Oncology (2022)

Abstract Background New approaches for 7 Tesla magnetic resonance spectroscopic imaging (MRSI) allow the simultaneous imaging of multiple neuro-oncological biomarkers with 3-4 mm resolution in clinically feasible measurement times. Specifically, the amino acids glutamine (Gln) and Glycine (Gly), were previously limited to single voxel detection at lower fields. Both could add to our capabilities to resolve heterogeneous tumour metabolism. Purpose To progress the validation of Gln and Gly as neuro-oncological markers by conducting the first comparison to amino acid PET in a cohort of glioma patients. Material and Methods In 24 glioma patients (WHO 2021 classification), we quantitatively compared 7T MRSI (3D, 3.4 mm isotropic resolution, 15 min scan time) and routine PET (FET or MET). Within manual tumour segmentations, we defined hotspot volumes of interest (VOI) for the ratios of total choline (tCho, clinical standard reference), Gln, Gly to total N-acetylaspartate (tNAA) and PET tumour-to-brain ratios (TBR), all with a cut-off threshold of 1.6. For these VOIs, we calculated VOI volumes and median ratios as well as Dice similarity coefficients (DSC) and centre of intensity distance (CoI), between MRSI and PET ratios. Results We found that Gln and Gly ratios to tNAA had a higher correspondence to PET-based amino acid metabolism than tCho. Our resulting median VOI volumes were 19.08±23.10 cm³ for tCho/tNAA, 33.68±24.60 cm³ for Gln/tNAA, and 22.38±18.49 cm³ for Gly/tNAA compared to 24.33±30.46 cm³ for PET, with correlation coefficients &amp;gt;0.5 for all MRSI hotspot values in relation to PET volumes. Median ratios were 0.52±0.13 for tCho/tNAA, 0.61±0.25 for Gln/tNAA, 0.33±0.15 for Gly/tNAA and 2.11±0.42 for PET. The median DSCs to PET amounted to 0.53±0.36 for tCho/tNAA, 0.66±0.40 for Gln/tNAA, and 0.57±0.36 for Gly/tNAA, while the median CoI distances were 0.56±0.43 cm for tCho/tNAA, 0.39±0.22 cm for Gln/tNAA, and 0.45±0.48 cm for Gly/tNAA. Conclusion With this first study that compared high-resolution 3D-MRSI at 7 Tesla to amino acid PET and a quantitative evaluation, we demonstrated that Gln and Gly corresponded better to PET than tCho, which is the main marker used in clinical MR, both within the study and compared to previous literature. Future research is needed to clearly define the benefits of 7T MRSI for neuro-oncology such as the identification of tumour microenvironments or non-invasive determination of molecular-pathologic markers. Gln could be further explored by the application of Gln-based PET tracers to MR-PET. We still see further developments of MRSI methods, such as motion correction or absolute quantification of concentrations instead of ratios, as necessary to obtain such goals.
P11.41.B The Cost of Inpatient Care For Adult Primary Brain Tumour Patients in England
Authors: N Kanso, K Le Calvez, R Mauricaite, M Williams
Journal: Neuro-Oncology (2022)

Abstract Background Primary brain tumours are rare, but are the cause of the most life-years lost of any cancer. Given their poor prognosis, questions about their treatment and care costs are important especially in publicly-funded healthcare systems. There is currently very little robust data on the cost of care for brain tumour patients. Here we present up-to-date estimations of the direct inpatient care costs of all adult primary brain tumour patients in England, with a specific breakdown of costs attributed to cranial glioblastomas and cranial meningiomas, the commonest primary brain tumours. Material and Methods GlioCova uses a linked English national cancer data on over 50,000 adult primary brain tumour patients diagnosed between 2013-2018, with data on secondary healthcare activities three months before diagnosis - the last three months of 2012, and follow-up data after diagnosis - up to the last admission of 2019. We examined inpatient care with a breakdown of costs attributed to different treatment types: neurosurgery, chemotherapy and radiotherapy. We used the NHS HRG4+ Reference Costs Grouper 2017/2018 to assign costs matched from the National Schedule of Reference Costs 2017/2018. We converted all values to 2021 using the Health CPI Index. Results There were a total of 51,775 adult primary brain tumour patients diagnosed in England in the 6 year period between 2013 and 2018. 48,608 of these were admitted to hospital between the last three months of 2012 and the end of 2019, of which we were able to assign costs to 47,521 patients (98%). Total inpatient costs for the whole brain tumour cohort were over £973 million during the time period (34% attributed to inpatient care for neurosurgery, chemotherapy, and radiotherapy). 14,691 (31%) of patients were diagnosed with a cranial glioblastoma, and 9,501 (20%) of patients were diagnosed with a cranial meningioma. Total inpatient costs were £349 million and £163 million for glioblastoma and meningioma respectively, with 34% again devoted to direct treatment costs. Conclusion The estimated direct inpatient care costs for all 51,775 primary brain tumour patients diagnosed in England between 2013 and 2018 were nearly £1 billion (£166 million/year cohort), 2/3 of which was not for direct treatment. This does not include outpatient chemotherapy and radiotherapy costs, other outpatient appointments, patient out-of-pocket costs, primary care, social care, or end-of-life care costs. Future work will examine variation in care and costs and extend the analysis to include outpatients. We hope these data will help make an economic argument for improving care for brain tumour patients. More information on GlioCova: https://blogs.imperial.ac.uk/gliocova/about-gliocova/.